The development of all pharmaceutical products requires the production of high purity drug substance preparations, pharmaceutical compositions and dosage forms that contain effective amounts of the active pharmaceutical ingredient (API), and minimal impurities. However, pharmaceutical products containing an API that must be dosed in large amounts for long periods of time, present a special challenge to drug manufacturers since, in such cases, the potential exposure of the patient to any impurities present in the pharmaceutical product is amplified.
All drug substance preparations, regardless of the API, contain finite amounts of impurities. These impurities can generally be grouped into categories based upon their chemical identity.
Impurities that are structurally similar to the API are commonly referred to as “product-related impurities.” In the case of APIs containing chiral centers where one enantiomer shows therapeutic effect, while the other enantiomer shows either no effect, minimal effect, or an undesirable effect, the latter enantiomer represents a type of product-related impurity, commonly referred to as an “enantiomeric impurity.”
Impurities that are not structurally similar to the API, and are introduced by the process(es) used to make the API, are commonly referred to as “process-related impurities.” Process-related impurities can comprise such things as unreacted starting materials, materials added to purify the API, by-products of side reactions, and the like, which do not structurally resemble the API. Process-related impurities may also comprise residual solvents and heavy metals. However, due to their known toxic properties, residual solvents and heavy metals are often considered apart from other types of process-related impurities.
Since drug substance preparations containing a given API are used to prepare pharmaceutical compositions, which, in turn are used to manufacture drug products for administration of the API, pharmaceutical compositions and drug products generally contain the product- and process-related impurities that co-occur with the given API in the starting drug substance preparations. In order to minimize risk to human health caused by impurities within drug products, governmental agencies establish specific limits for various types of impurities that arise in final drug products from the API-containing drug substance preparations. Drug substance preparations and excipients must typically have impurity levels that are equal to or less than these limits, in order for manufacturers to gain governmental approval to market and sell their drug products.
As with drug substance preparations of any synthetic organic API, drug substance preparations of (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid (USAN and INN name: tarenflurbil) can contain product-related impurities (e.g., (S)-(+)-2-(2-fluoro-4-biphenylyl) propionic acid), process-related impurities, residual solvents, and heavy metals. Since there is a need for pharmaceutical dosage forms containing (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid as the API, and since the API in these dosage forms may require administration in relatively large amounts for extended periods of time, there is a clear need for (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid-containing pharmaceutical compositions and dosage forms made from (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid drug substance preparations containing acceptable levels of impurities of all types.